Atorvastatin, e.g., LIPITOR™, is used as a selective and competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols such as cholesterol. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in cholesterol biosynthesis. Atorvastatin is indicated, in conjunction with dietary restriction, in the management of hyperlipidemia, including hypercholesterolemia, mixed dyslipidemia, and homozygous familial hypercholesterolemia.
(R)-ethyl 4-cyano-3-hydroxybutyrate is a key intermediate in the synthesis of atorvastatin.
Crosby, John A.; Parratt, Julian S.; Turner, Nicholas J., Dep. Chem., Univ. Exeter, Exeter, UK. Tetrahedron: Asymmetry (1992), 3(12), 1547-1550, reported enzymatic hydrolysis of prochiral dinitriles, where a series of prochiral 3-hydroxyglutaronitrile derivatives were enzymatically hydrolyzed to corresponding nitrile-carboxylic acids with enantiomeric excesses of 22% to 84%. The products were of the (S)-configuration in all cases.
Effenberger, Franz; Osswald, Steffen., Institut fur Organische Chemie, Universitat Stuttgart, Stuttgart, Germany. Synthesis (2001), (12), 1866-1872, reported selective hydrolysis of aliphatic dinitriles to monocarboxylic acids by a nitrilase from Arabidopsis thaliana expressed in E. coli. Conversion rate and selectivity of the hydrolysis of dinitriles w-cyanocarboxylic acids depended on the chain length.